tbuckley/cabot-search huggingface dataset:
Abstract 3731: The polyamine-hypusine circuit controls an oncogenic translational program essential for malignant transformation in MYC-driven lymphoma
Authors: Shima Nakanishi, Jiannong Li, Anders E. Berglund, Youngchul Kim, Yonghong Zhang, Ling Zhang, Chunying Yang, Raghavendra G. Mirmira, John L. Cleveland
Journal: Cancer Research (2023)

Abstract The MYC oncoprotein is activated in a broad spectrum of human malignancies and transcriptionally reprograms the genome to drive cancer cell growth. Given these functions, it is unclear if targeting a single effector of MYC will have therapeutic benefit. MYC activates the polyamine-hypusine circuit, which post-translationally modifies a single lysine residue (Lys-50) of eukaryotic translation initiation factor eIF5A in a process coined hypusination via two enzymes,deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). The roles of this circuit in cancer are unclear. Here we report essential intrinsic roles for hypusinated eIF5A in the development and maintenance of MYC-driven lymphoma, where loss of eIF5A hypusination completely abolishes malignant transformation of MYC-overexpressing B cells in transgenic mice predestined to develop lymphoma. Mechanistically, integrating RNA-seq, Ribo-seq and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including regulators of G1-to-S phase cell cycle progression and DNA replication. Thus, this circuit controls MYC’s proliferative response at several levels and is activated in many tumor types. These findings suggest the hypusine circuit as a therapeutic target for a broad spectrum of malignancies. Citation Format: Shima Nakanishi, Jiannong Li, Anders E. Berglund, Youngchul Kim, Yonghong Zhang, Ling Zhang, Chunying Yang, Raghavendra G. Mirmira, John L. Cleveland. The polyamine-hypusine circuit controls an oncogenic translational program essential for malignant transformation in MYC-driven lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3731.
Abstract 5585: Tissue based next generation sequence is more accurate than ctDNA to detected pathogenic variants in <i>MTAP</i> wild type tumors
Authors: Andre Luiz De Souza
Journal: Cancer Research (2023)

Abstract Next generation sequencing (NGS) of circulating tumor DNA (ctDNA) prevents invasive biopsies and captures tumor heterogeneity. In a prior report by Zhang et al (Nat Commun 2021), certain actionable mutations were more prevalent in ctDNA than tissue-based databases (e.g., EGFR 48% versus 25.2%). Our group investigated if discrepancies in patterns of pathogenic variants between liquid biopsy and tissue specimens in a subtype of metastatic urothelial carcinoma (MTAP deleted) can inform the best approach of utilizing tissue or blood. MTAP (methyl-adenosine phosphorylase) is an enzyme involved in salvage purine biosynthesis and its deletion confers sensitivity to pemetrexed and taxanes, but resistance to immune checkpoint inhibitors. The MTAP gene is deleted in 25% of urothelial carcinomas. We report herein the pattern of pathogenic variants from ctDNA in 17 patients with metastatic urothelial carcinoma, 10 with MTAP-deletion and 17 with MTAP wild-type. Among 10 patients with MTAP-deleted urothelial carcinoma with collected ctDNA, 3 had no detected pathogenic variant. The most common pathogenic variants in 7 patients were TP53 (4/7, 57%), TERT (4/7, 57%), ERBB2 (2/7, 28%); PIK3CA (2/7, 28%), and NFE2L2 (2/7, 28%). The mutations found in paired ctDNA and tissue based NGS were TP53 in 26.6 % (4/15), TERT in 21.0 % (4/19), ERBB2 in 66.6 % (2/3), PIK3CA in 50 % (2/4), and NFE2L2 in 100% (1/1) of patients. Three of the 10 patients with collected ctDNA had ELF3 frameshift loss-of- function alterations on tissue not found on ctDNA. Among 54 patients with MTAP wild-type urothelial carcinoma, 26 had collected ctDNA. Among these 26 patients, 9 had no detected pathogenic variants. Among the 17 patients with pathogenic variants, the most common mutations were TP53 (76%, 13/17), TERT (47%, 8/17), ERBB2 (24%, 4/17), RB1 (24%, 4/17), and BRCA1 or BRCA2 (24%, 4/17). Three of these 17 patients had no or insufficient tissue for NGS. The mutations found in paired ctDNA and tissue based NGS were TP53 in 100% (14/14), TERT in 64% (9/14), ERBB2 in 43% (6/14), RB1 in 29% (5/14), and BRCA1 or BRCA2 in 36% (5/14) of patients. MTAP wild-type patients had a higher frequency of TERT alterations (p=0.012), but not ERBB2, (p=0.453) than patients with MTAP-deleted type tumors. Ongoing evaluation of timing and location of pathogenic variants will inform where (primary tumor, metastatic site) and when (after chemotherapy, immune checkpoint inhibitors, antibody drug conjugates) to biopsy patients on progression after cancer therapies. Citation Format: Andre Luiz De Souza. Tissue based next generation sequence is more accurate than ctDNA to detected pathogenic variants in MTAP wild type tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5585.
Abstract 6334: VBI-002, a CD47xICAM-1 bispecific antibody for the treatment of hepatocellular carcinoma, melanoma and non-small cell lung cancers
Authors: Oi Kwan Wong, Xinhua Wang, Leonard Post, Xiaocheng Chen
Journal: Cancer Research (2023)

Abstract Intercellular Cell Adhesion Molecule 1 (ICAM-1, CD54) is a type I transmembrane protein and a member of the immunoglobulin superfamily. ICAM-1 is involved in many key processes such as cell-cell interactions, signal transduction and leukocytes trans-endothelial migration. ICAM-1 is constitutively present at low levels on healthy tissues but highly expressed in some hematological cancers and solid tumors, making it an attractive tumor target. VBI-002 is a novel human IgG1 based CD47xICAM-1 bispecific antibody with excellent safety profile and potent single agent activities in xenograft models of lymphoma, multiple myeloma and some solid tumors (Cancer Res 2022;82(12_Suppl):Abstract nr 3430). The bispecific design allows VBI-002 to selectively block CD47/SIRPα binding in tumor cells with high ICAM-1 expression. In contrast to the benchmark CD47 monoclonal antibody, VBI-002 exhibits minimal red blood cell binding and does not cause hemagglutination. In non-human primate (NHP) safety study, four weekly doses of 60 mg/kg VBI-002 were well-tolerated with only mild and reversible reduction in hemoglobin and platelets. Here we further investigate the anti-tumor activities of VBI-002 in solid tumors. Gene expression analysis suggested that ICAM-1 is highly expressed in non-small cell lung cancers (NSCLC), melanoma and a subset of hepatocellular carcinoma. Flow cytometry studies confirmed the frequent co-expression of ICAM-1 and CD47 in these tumors. VBI-002 has potent ICAM-1 dependent SIRPα blocking, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity activities against cell lines of NSCLC, hepatocellular carcinoma, and melanoma. Furthermore, in vivo efficacy studies demonstrated that VBI-002 has potent single agent activities in cell line derived xenograft (CDX) models of NSCLC, hepatocellular carcinoma, and melanoma. Weekly dose of 20 mg/kg VBI-002 is sufficient to stop tumor growth or drive tumor regression in most models. Notably, VBI-002 is highly effective against NSCLC CDX models carrying Kras mutation and it synergizes with paclitaxel to provide additional anti-tumor activity. In conclusion, VBI-002 is a versatile novel CD47xICAM-1 bispecific antibody with potent single agent activity in various solid tumors and combined well with standard of care chemotherapies for added activity. Thus, VBI-002 warrants clinical evaluations as a single agent and in combination with standard of care chemotherapies. Citation Format: Oi Kwan Wong, Xinhua Wang, Leonard Post, Xiaocheng Chen. VBI-002, a CD47xICAM-1 bispecific antibody for the treatment of hepatocellular carcinoma, melanoma and non-small cell lung cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6334.
Abstract 6284: SUV420H1 as a novel target in HPV-negative head and neck squamous cell carcinoma
Authors: Arfa Moshiri, Hui Cheng, Sohyoung Kim, Vassiliki Saloura
Journal: Cancer Research (2023)

Abstract Human Papilloma Virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type in the world and its outcomes are mostly unchanged for the past few decades, especially for HPV-negative HNSCC. The TCGA recently revealed a plethora of genetic alterations in chromatin modifiers in HPV-negative HNSCC, including protein lysine methyltransferases which methylate lysine residues on histone tails and regulate gene expression. One of these enzymes, SUV420H1, is known to trimethylate H4K20 and is recurrently amplified in approximately 6% of HPV-negative HNSCC tumors (TCGA). It has also been found to be significantly overexpressed in multiple HNSCC cell lines compared with normal keratinocytes. This study aims to investigate whether SUV420H1 has oncogenic activity and could be a novel therapeutic target in HPV-negative HNSCC. To evaluate the effect of SUV420H1 depletion on HPV-negative HNSCC cell lines, siRNA-mediated knockdown was performed in four SUV420H1 overexpressing HPV-negative HNSCC cell lines, and MTT assays showed significantly reduced cell viability by approximately 80-90% after 12 days of siRNA treatment. Colony formation assays, cell cycle analysis and apoptosis assays are ongoing, and these assays are planned in SUV420H1 CRISPR KO cell lines. Gene Set Enrichment Analysis in 434 HPV-negative HNSCC tumors (TCGA) showed significant enrichment of immune signatures, EMT, cell cycle and apoptosis pathways. Ongoing experiments aim to investigate the effects of SUV420H1 knockdown on the global histone methylome, and to identify direct downstream targets of SUV420H1 through combined genome-wide mapping of SUV420H1 using CUT&amp;RUN assays and RNA-seq in HPV-negative HNSCC cell lines. Syngeneic and xenograft mouse models are also planned to evaluate the effect of SUV420H1 depletion on flank tumor growth in vivo. These studies may elucidate the oncogenic effects and mechanisms of SUV420H1, and may provide evidence to support SUV420H1 as a potential novel target in the treatment of HPV-negative HNSCC tumors with SUV420H1 amplification or overexpression. Citation Format: Arfa Moshiri, Hui Cheng, Sohyoung Kim, Vassiliki Saloura. SUV420H1 as a novel target in HPV-negative head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6284.
Abstract 629: Characterization of the molecular mechanism of APOC1 in anti-ferroptosis and lymph node microenvironment remodeling in ESCC metastasis process
Authors: Beilei Liu, Baifeng Zhang, Hongyu Zhou, Licheng Tan, Xiaona Fang, Lanqi Gong, Jie Luo, Jinlin Huang, Jiao Huang, Yuma Yang, Xinyuan Guan
Journal: Cancer Research (2023)

Abstract The invasion and metastasis affect the survival and prognosis of patients with esophageal carcinoma (ESCC). Through single-cell sequencing analysis of para-cancerous tissue, tumor tissue, normal lymph node tissue and lymph node metastasis tissue in 4 untreated ESCC patients, we found that APOC1 was specifically up-regulated in lymph node metastasis tissue and tumor tissue. In vitro and in vivo experiments revealed that APOC1 overexpression significantly promoted the migration and anti-ferroptosis function in ESCC. Also, APOC1 upregulation promotes M2 macrophage differentiation, Treg aggregation, and CD8 T cell immune inactivation in lymph node metastasis tissue. Mechanistically, APOC1 competes with NRF2 to bind Keap1, promoting nuclear translocation of NRF2 thus upregulating activation of the NRF2 pathway in tumor cells. For the lymph node metastasis tumor microenvironment, secreted APOC1 could upregulate the oxLDL which induced M2 macrophage polarization via CD36/JAK2/STAT3 axis. Overall, in this study, we explored the role and molecular mechanism of APOC1 in ESCC metastasis process which could provide a new molecular therapeutic approach to ESCC patients. Citation Format: Beilei Liu, Baifeng Zhang, Hongyu Zhou, Licheng Tan, Xiaona Fang, Lanqi Gong, Jie Luo, Jinlin Huang, Jiao Huang, Yuma Yang, Xinyuan Guan. Characterization of the molecular mechanism of APOC1 in anti-ferroptosis and lymph node microenvironment remodeling in ESCC metastasis process [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 629.
Abstract 3800: The disruption of miR-125b-SLC1A5 cascade defines the oncogenicity and differential immune profile in oral carcinoma
Authors: Ying-Chieh Liu, So-Yu Liu, Yu-Cheng Lin, Chung-Ji Liu, Kuo-Wei Chang, Shu-Chun Lin
Journal: Cancer Research (2023)

Abstract Head and neck squamous carcinoma (HNSCC) including oral SCC (OSCC) is a worldwide malignancy that requires vigorous efforts for interception. The metabolic reprogramming sustains malignant tumor cells to overcome stressful microenvironments. As the glutamine is the one of the essential components which helps cells to erase reactive oxygen species and energy production, the increased uptake of glutamine is a common metabolic hallmark in cancers. Bioinformatic analysis of TCGA HNSCC datasets and RNAseq results in our cohort indicated that solute carrier family 1 member 5 (SLC1A5) is the most eminently dysregulated transporter member among the seven glutamate or neutral amino acid transporters in SLC1A family. This work identified that the knockdown of SLC1A5 expression decreased in vitro oncogenicity, xenografic tumorigenesis and glutamine uptake; increased oxidative stress, cell cycle arrest, and sensitivity to cisplatin and ferroptosis inducer in OSCC cells. By way of contrast, the upregulation of endogenous SLC1A5 expression mediated by CRISPR/dCas9 activation system drove the OSCC oncogenesis. The reporter assay and functional analysis demonstrated that suppressor miRNA miR-125b targeted and attenuated SLC1A5, while NEAT1 lncRNA sponged and ablated miR-125b-SLC1A5 axis. The analysis of TCGA and GEO datasets confirmed the concordant upregulation of NEAT1 and downregulation of miR-125b along with the SLC1A5 upregulation in tumors. Besides, SLC1A5 upregulation defined the worse HNSCC patient survival. In our tumor cohort, OSCC harboring higher SLC1A5 expression had lower CD4+ immune score, and higher scores in M0 and M1 macrophage. GSEA algorithm further deciphered that tumors having higher SLC1A5 expression manifested the repression in glycolysis, apoptosis and p53 signaling. This study concludes that the frequent disruption of NEAT1-miR-125b-SLC1A5 cascade modulates the pluripotent oncogenic activities, the treatment efficacy and the immune landscape in oral carcinoma. Citation Format: Ying-Chieh Liu, So-Yu Liu, Yu-Cheng Lin, Chung-Ji Liu, Kuo-Wei Chang, Shu-Chun Lin. The disruption of miR-125b-SLC1A5 cascade defines the oncogenicity and differential immune profile in oral carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3800.
Abstract 6348: ABN202 (αEGFR-interferon-β mutein), a potent antibody-cytokine fusion protein for the treatment of EGFR-positive non-small cell lung cancer
Authors: Heegeon Park, Saehyung Lee, Hayeon Park, Sunghyun Hong, Jaemun Kim, Sungyoul Hong, Ji-hyun Park, Young Kee Shin, Jun Young Choi, Na Young Kim
Journal: Cancer Research (2023)

Abstract ABN202 is an antibody-cytokine fusion protein consisting of interferon-β mutein (ABN102) molecularly fused to a anti-EGFR monoclonal antibody that recognizes the EGFR expressed on various types of cancer cells. In previous studies, we developed ABN102, a bio-better version of recombinant human interferon-β with hyperglycosylation via site-directed mutagenesis to improve stability, productivity, and pharmacokinetics properties. An addition of glycosylation at the N25 residue of ABN102 is expected to reduce the peripheral toxicity of ABN202, as it can shield the IFNAR2 binding interface. In this study, the binding ability and biological activity of ABN202 was evaluated in vitro models. ABN202 downregulates the EGFR protein expression and reduces EGFR phosphorylation by degrading target proteins via internalization in the EGFR-positive NSCLC cell line. In addition, we also determined the direct and indirect anti-cancer activity of ABN202 in preclinical models. Taken together, we suggest that ABN202 has potent anti-cancer activities, via direct cytotoxicity in EGFR-positive tumors and indirectly activating immune cells through Type I IFN signaling. we conclude ABN202 is a promising drug candidate for patients with EGFR-positive NSCLC. Citation Format: Heegeon Park, Saehyung Lee, Hayeon Park, Sunghyun Hong, Jaemun Kim, Sungyoul Hong, Ji-hyun Park, Young Kee Shin, Jun Young Choi, Na Young Kim. ABN202 (αEGFR-interferon-β mutein), a potent antibody-cytokine fusion protein for the treatment of EGFR-positive non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6348.
Abstract 1006: Assessment of expression of microRNA-23b as a prognostic marker in cancer
Authors: Ahmed Mahmoud Wadaaallah, Ahmed Samir Sultan
Journal: Cancer Research (2023)

Abstract Cancer is the major cause of death around the world. MiRNA-23b has been proposed to be expressed in various types of cancer. However, it’s prognostic role in several types of cancer has not been well identified. We conducted this meta-analysis to assess the associations between miRNA-23b expression and overall survival (OS) in various carcinoma. The current study presented the baseline characteristics and pooled survival results using a pooled hazard ratio (HR) with 95% confidence intervals (95% CI). Both Random and fixed effect models were conducted according to the heterogeneity of the analyzed. Then subgroup and publication bias analyses were executed. We identified a total sample size of 1589 in various carcinomas, including gastric (370), breast (203), ovarian (166), colorectal (206), renal (411), bladder (20), prostate (151) and lung cancer (62). The pooled HR of nine studies suggested that low miRNA-23b expression was obviously associated with worse OS (HR 3.2, 95% CI 2.26 to 4.53, P&amp;lt;0.001) with a low statistical heterogeneity index (I2=53%, P=0.03) in most of cancer types. On the other hand, the other three remaining studies (gastric and breast cancer) showed that miRNA-23b high expression was associated with reduced OS (HR 1.59, 95%CI 1.07 to 2.37, P&amp;lt;0.02) with no heterogeneity between the studies (I2=0%, P=0.38). All in all, our data showed that miRNA-23b was highly expressed in the plasma of breast and gastric cancer but was low expressed in most types of cancer. In addition, miRNA -23b expression is significantly associated with poor overall survival in several cancer types and might be considered as a potential prognostic marker. Citation Format: Ahmed Mahmoud Wadaaallah, Ahmed Samir Sultan. Assessment of expression of microRNA-23b as a prognostic marker in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1006.
Abstract 5264: Cucurbitacin D modulates the Nrf2 signaling pathway and protects against benzo[a]pyrene-induced liver injury
Authors: Shabnam Malik, Anyssa Rodriguiez, Mohammed Sikander, Daniel Zubieta, Fathi T. Halaweish, Subhash C. Chauhan, Meena Jaggi
Journal: Cancer Research (2023)

Abstract Background: Accumulating studies have shown strong correlation of HCC and co-morbidity factors including smoking. Tobacco smoke contains benzo[a]pyrene, which is extremely carcinogenic and contributes to liver damage. Cucurbitacin, a triterpene, has a wide range of biological activities, including antioxidant, anti-inflammatory, and anti-cancer properties. However, their hepatoprotective effects remain poorly understood. In the current study, we examined the hepatoprotective activity of cucurbitacin D, a novel analog of cucurbitacin, against benzo[a]pyrene-induced liver injury in human HepG2 cells. Method: To investigate the hepatoprotective effect of cucurbitacin D against benzo[a]pyrene-induced liver damage, proliferation, clonogenicity, migration, invasion, Western blotting, and qPCR analyses were performed. The DCFDA assay was performed to determine the level of intracellular reactive oxygen species (ROS) in liver cells. Results: Functional assays showed that cucurbitacin D exhibited cytoprotective effects against dose-dependent growth inhibition by benzo[a]pyrene in human HepG2 cells. This protective effect was likely associated with antioxidant potential of cucurbitacin D, as evidenced by the attenuation of ROS observed by fluorimeter and fluorescence microscopy. Western blotting analysis demonstrated Cucurbitacin D targets Nrf-2 signaling pathway and associated effector proteins including HO-1 and LC3A in protecting liver cells against benzo[a]pyrene induce oxidative damage. Further studies are underway to understand the underlying molecular mechanism of action. Conclusion: These findings demonstrate the hepatoprotective effects of cucurbitacin D against benzo[a]pyrene-induced liver damage, making it a promising ingredient for nutritional supplements. Citation Format: Shabnam Malik, Anyssa Rodriguiez, Mohammed Sikander, Daniel Zubieta, Fathi T. Halaweish, Subhash C. Chauhan, Meena Jaggi. Cucurbitacin D modulates the Nrf2 signaling pathway and protects against benzo[a]pyrene-induced liver injury. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5264.